Abstract: Objective  To investigate the therapeutic effect of different doses of exosomes derived from bone marrow mesenchymal stem cells (BMSCs) on peritoneal fibrosis, and to find out the optimal therapeutic dose and timing of BMSCs exosome therapy.  Methods  A mouse model of peritoneal fibrosis induced by high concentration of glucose in peritoneal dialysate was established and divided into the normal control group, exosome group, peritoneal fibrosis group and peritoneal fibrosis + exosome group. The exosome group was treated by giving exosomes at 6 time points and 4 different exosome doses to determine the optimal therapeutic dose and timing.  Results  Pathological changes of peritoneal fibrosis in the mouse model induced by high concentration of glucose in peritoneal dialysate were observed at the 28th day and became worse with prolongation of the treatment, suggesting that the BMSCs exosome therapy may be preferable from the 28th day. Administration of the exomes at the 28th day, peritoneal thickness and collagen I expression had no differences between the exomes 50 μg/kg and 100 μg/kg groups (t=0.540, P=0.705; t=1.031, P=0.360) but peritoneal fibrosis alleviated significantly in exomes 200 μg/kg and 400 μg/kg groups (t=5.071, P=0.005; t=5.226, P=0.005), as compared with those in the peritoneal fibrosis group. However, there was no significant difference in improvement of peritoneal fibrosis between exomes 200 μg/kg group and 400 μg/kg group (t=1.540, P=0.280). These results suggested that exomes 200 μg/kg may be the optimal dosage of peritoneal fibrosis therapy. Further exploration of the timing of exosome therapy showed that peritoneal thickening could be significantly reduced by the exosome therapy at the 28th day or at the 35th day (t=4.608, P=0.007; t=4.608,  P=0.007), and exosome therapy at the 28th day plus at the 35th day was more effective than the single treatment at the 28th day or at the 35th day (t=5.730, P=0.003; t=5.730, P=0.003). These results suggested that the optimal exosome therapy was given at the 28th day plus at the 35th day for mouse peritoneal fibrosis model.  Conclusion  This study showed that the optimal treatment time of BMSCs exosomes for peritoneal fibrosis mice model was preferable at the 28th day plus at the 35th day, and the optimal dose was 200 μg/kg.

Key words: Exosome, Peritoneal dialysis, Peritoneal fibrosis, Timeliness, Dose-effectiveness